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Royal Marsden Hospital, London, UK
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Checkpoint inhibitors are now widely used in the management of many cancers. Endocrine toxicity is amongst the most common side effects. These endocrinopathies differ from most other immune-related toxicities in frequently being irreversible and rarely requiring cessation of checkpoint inhibitor therapy. This review considers an approach to the presentation and diagnosis of endocrinopathies, compared to classical endocrine diagnosis, suggesting improvements to classification and treatment based on fundamental endocrine principles. These will help to align management with other similar endocrine conditions and standardise the diagnosis and reporting of endocrine toxicity of checkpoint inhibitors to improve both endocrine and oncological care. In particular, the importance of considering any inflammatory phase (such as painful thyroiditis or hypophysitis resulting in the pituitary enlargement), from the endocrine consequences (transient hyperthyroidism followed by hypothyroidism, pan-hypopituitarism or isolated adrenocorticotrophic hormone deficiency), is highlighted. It is also important to consider the potential confounder of exogenous corticosteroids in adrenal suppression.
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Imperial College London, Institute of Reproductive and Developmental Biology, London, UK
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Malmö University Hospital, Reproductive Medicine Center, Malmö, Sweden
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Objective
During androgen ablation in prostate cancer by the standard gonadotropin-releasing hormone (GnRH) agonist treatment, only luteinizing hormone (LH) is permanently suppressed while circulating follicle-stimulating hormone (FSH) rebounds. We explored direct prostatic effects of add-back FSH, after androgen ablation with GnRH antagonist, permanently suppressing both gonadotropins.
Methods
The effects of recombinant human (rFSH) were examined in mice treated with vehicle (controls), GnRH antagonist degarelix (dgx), dgx + rFSH, dgx + flutamide, or dgx + rFSH + flutamide for 4 weeks. Prostates and testes size and expression of prostate-specific and/or androgen-responsive genes were measured. Additionally, 33 young men underwent dgx-treatment. Seventeen were supplemented with rFSH (weeks 1–5), and all with testosterone (weeks 4–5). Testosterone, gondotropins, prostate-specific antigen (PSA), and inhibin B were measured.
Results
In dgx and dgx + flutamide treated mice, prostate weight/body weight was 91% lower than in controls, but 41 and 11%, respectively, was regained by rFSH treatment (P = 0.02). The levels of seminal vesicle secretion 6, Pbsn, Nkx3.1, beta-microseminoprotein, and inhibin b were elevated in dgx + rFSH-treated animals compared with only dgx treated (all P < 0.05). In men, serum inhibin B rose after dgx treatment but was subsequently suppressed by testosterone. rFSH add-back had no effect on PSA levels.
Conclusions
These data provide novel evidence for the direct effects of FSH on prostate size and gene expression in chemically castrated mice. However, in chemically castrated men, FSH had no effect on PSA production. Whether FSH effects on the prostate in humans also require suppression of the residual adrenal-derived androgens and/or a longer period of rFSH stimulation, remains to be explored.
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Objective
Multiple endocrine neoplasia type 4 (MEN4) is caused by a CDKN1B germline mutation first described in 2006. Its estimated prevalence is less than one per million. The aim of this study was to define the disease characteristics.
Methods
A systematic review was performed according to the PRISMA 2020 criteria. A literature search from January 2006 to August 2022 was done using MEDLINE® and Web of ScienceTM.
Results
Forty-eight symptomatic patients fulfilled the pre-defined eligibility criteria. Twenty-eight different CDKN1B variants, mostly missense (21/48, 44%) and frameshift mutations (17/48, 35%), were reported. The majority of patients were women (36/48, 75%). Men became symptomatic at a median age of 32.5 years (range 10–68, mean 33.7 ± 23), whereas the same event was recorded for women at a median age of 49.5 years (range 5–76, mean 44.8 ± 19.9) (P = 0.25). The most frequently affected endocrine organ was the parathyroid gland (36/48, 75%; uniglandular disease 31/36, 86%), followed by the pituitary gland (21/48, 44%; hormone-secreting 16/21, 76%), the endocrine pancreas (7/48, 15%), and the thyroid gland (4/48, 8%). Tumors of the adrenal glands and thymus were found in three and two patients, respectively. The presenting first endocrine pathology concerned the parathyroid (27/48, 56%) and the pituitary gland (11/48, 23%). There were one (27/48, 56%), two (13/48, 27%), three (3/48, 6%), or four (5/48, 10%) syn- or metachronously affected endocrine organs in a single patient, respectively.
Conclusion
MEN4 is an extremely rare disease, which most frequently affects women around 50 years of age. Primary hyperparathyroidism as a uniglandular disease is the leading pathology.